1. Field of the Invention
The present invention relates generally to the fields of medicine and oncology. More particularly, it concerns methods for the identification and treatment of PARP inhibitor-resistant cancers.
2. Description of Related Art
Increased levels of reactive oxygen species (ROS) in cancer cells can cause oxidative DNA damage that leads to genomic instability and tumor development (Irani et al., 1997; Trachootham et al., 2009; Radisky et al., 2005; Lindahl, 1993). ROS-induced DNA damage, such as a single-strand breaks, recruits PARP1 to the lesion sites to orchestrate the DNA repair process through poly ADP-ribosylation (PARylation) on itself and its target proteins (Luo and Kraus, 2012; Gibson and Kraus, 2012). PARP inhibitors have been widely evaluated in clinical trials since the discovery of synthetic lethality of PARP inhibition in BRCA-mutant cancer cells, which are deficient in the repair machinery of the double-strand DNA damage (Farmer et al., 2005; Bryant et al., 2005).
In addition, PARP inhibitors are also being investigated in clinical trials for triple-negative breast cancer (TNBC) as it has been reported to possess BRCAness properties (Hampson et al., 2010; Turashvili et al., 2011), such as BRCA mutations, methylations in the BRCA1 promoter, and dysregulation of the BRCA pathway. TNBC is an aggressive subtype of breast cancer that initially responds to chemotherapy, but a majority of TNBCs eventually develop resistance. Moreover, there are no approved targeted therapies to treat TNBC, unlike other breast cancer subtypes, such as those positive for estrogen receptor (ER) and/or HER2, for which specific inhibitors are available. More than 100 clinical trials testing PARP inhibitors are underway, and the U.S. Food and Drug Administration recently approved the PARP inhibitor olaparib (Lynparza™, AstraZeneca) for the treatment of patients with BRCA-mutated ovarian cancer, and there are multiple ongoing clinical trials of this drug targeting different cancer types. While encouraging results were reported in TNBC cancer patients carrying BRCA mutations (Tutt et al., 2010), such results were not observed in another trial (Gelmon et al., 2011). These clinical observations raise an important question of how to increase the response rate in TNBC or other cancer types. Thus, methods for increasing the response rate to PARP inhibitors and identifying the group of patients who will respond to PARP inhibitors are needed to stratify patients during treatment.